Development and clinical indications of PARP inhibitors

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Published: 25 Apr 2018
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Dr Mark O'Connor - AstraZeneca, Cambridge, UK

Dr O’Connor speaks with ecancer at AACR 2018 about the development and application of PARP inhibitors, such as olaparib, for ovarian and breast cancers.

He describes his research in treatment tolerability and the overlap of efficacy with observed PARP trapping.

For more on PARP inhibitors watch our interview with Dr Elisabetta Leo here.

I started working on PARP inhibitors when I was at KuDOS Pharmaceuticals, it’s the company that first discovered olaparib. I was working from 2004 all the way through and I’m still working on PARP inhibitors.

Why are you investigating PARP trapping?

The first PARP inhibitor went into patients in 2005, that was the first monotherapy approach. Clearly, since then olaparib has been approved, a number of other PARP inhibitors have been approved, but we’re still trying to understand the mechanisms both in terms of efficacy and tolerability. There are more PARP inhibitors coming through so it’s really important that we understand the science. What we’ve been doing is we’ve been trying to further investigate the importance of PARP trapping, which is a key component of the mechanism of action, but also what’s driving the different tolerability profiles.

How has this progressed and how will it move forward?

To date there’s really only long-term efficacy data for olaparib because it’s been in the clinic for such a long time but what’s becoming clear is that long-term efficacy is going to be a combination of both the initial efficacy but also the ability to continually inhibit PARP to more than 95% continuously. So if you have to have drug holidays or you have to dose reduce because of tolerability then there’s the potential that the tumours could grow out on treatment. So what we’ve been trying to do is understand the basis of tolerability and the safety profiles. That really comes down to three components: the first is specificity against the different PARP family members. So there are seventeen different PARPs, all of the clinically relevant PARP inhibitors have in common targeting of PARP1 but a number of other PARPs might be inhibited. The second component is secondary pharmacology and we think that can explain some of the adverse events outside of bone marrow and GI toxicity which is consistent between the different PARP inhibitors. The third component, which is quite interesting, is bone marrow penetrance. So, again, if you have a much higher level of penetrance into the bone marrow the potential is that you’ll have more bone marrow toxicity.

Do you find many misconceptions in this realm of work?

One of the really interesting aspects is for quite a while there were some suggestions that PARP trapping efficacy correlated with clinical efficacy. But what myself, Yves Pommier, Johann de Bono published in a Science Translational Medicine review was that as long as you have sufficient levels of PARP trapping actually the efficacy that’s being seen in the clinic for a number of PARP inhibitors is pretty similar. So, as I say, the early PARP inhibitor efficacy is dependent on sufficient PARP trapping but longer-term efficacy is going to be down to having a good tolerability profile.